Developmental and/or chronic lung diseases include adult chronic obstructive lung disease (COPD) such as cystic fibrosis and emphysema, and bronchopulmonary dysplasia of infant or premature baby. The seriousness of these diseases is that there are no effective prevention and treatment methods for these diseases in spite of the severeness and chronicity thereof.
For example, the bronchopulmonary dysplasia is a chronic lung disease induced by respiratory failure in newborn- or premature babies kept in a ventilator. Recent data for treating premature babies show an increase in the incidence of said untreatable diseases (Avery M E et al., Pediatrics 79:26-30, 1987). Not only the disease is a major cause of death of newborn infants, particularly, premature babies, but also surviving babies have to be hospitalized for a long period of time and serious side effects such as pulmonary hypertension must be dealt with. Even after discharge from the hospital, the rate of re-hospitalization of infants suffering from bronchopulmonary dysplasia is usually more than 50% because of their bronchopulmonary dysplasia due to their susceptibility to viral acute bronchiolitis and pneumonia. It is also known that bronchopulmonary dysplasia may progress to bronchial asthma because of continuous bronchial hyper-sensitivity (Coalson J J. Semin Neonatol, 8:73-81, 2003), and is further associated with a serious neurodevelopmental sequela such as cerebral palsy (Bregman J and Farrell E E, Clin Perinatol, 19:673-94, 1992).
An effective treatment method for bronchopulmonary dysplasia as well as other chronic lung disease of adults has not yet been developed. Studies have been focused on an approach for the treatment of bronchopulmonary dysplasia to reduce barotrauma and volutrauma caused by positive pressure ventilation or reduce oxygen concentration during the artificial ventilation treatment of newborn- and premature babies, besides the fact that steroids have been used to prevent and treat inflammation of the damaged lung. However, steroid treatment is now limited due to the recent reports suggesting that the use of steroid are associated with later abnormal neurodevelopmental prognosis, especially with the increase in cerebral palsy (Committee on Fetus and Newborn, Pediatrics, 109:330-8, 2002).
Recently anticipation has been rising for the treatment using stem cells having a potential to be differentiated into every organs. However, the transplantation of embryonic stem cells, which have excellent differentiation potential, has serious developmental problems caused by the generation of uncontrollable teratoma or genomic imprinting as well as ethical problems. Therefore, the application of embryonic stem cells has become limited, and instead, adult stem cells have recently attracted much interest for the treatment thereof.
Among adult stem cells, the stem cells of hematopoietic system have received much attention. The bone marrow-derived stem cells as a source for stem cells of hematopoietic system are generally grouped into two: hematopoietic stem cells and mesenchymal stem cells.
It has been known that the hematopoietic stem cells in bone marrow have plasticity, suggesting that they are differentiated into not only cells of hematopoietic system but also other various organ cells (Gussoni E et al. Nature., 401:390-394, 1999; Petersen B E et al., Science, 284:1168-1170, 1999; Mezey E et al., Science, 290:1779-1782, 2000; and Krause D S et al., Cell., 105:369-377, 2001). However, it is though not very common so that there is a doubt of biological usefulness. Some reports suggest that such phenomena might result from cell fusion (Wagers A J et al., Science, 297:2256-2259, 2002).
On the other hand, mesenchymal stem cells separated from bone marrow of adult mice, named ‘multipotent adult progenitor cells (MAPC)’, are capable of differentiating into all three germ layers of ectoderm, mesoderm and endoderm, and in fact they have proven to differentiate into almost all organ cells when injected into the blastocyst of a mouse. These cells were reported to have embryonic stem cell markers such as OCT-4, Rex-1 and SSEA-1 (Jiang Y et al., Nature, 418:41-49, 2002).
It has been much noted that similar stem cells separated from human bone marrow can be used for cell therapy for various diseases and damages (Reyes M et al., Blood, 98:2615-2625,2001; and Woodbury D et al., J Neurosci Res., 61:364-370, 2000). However, the numbers of hematopoietic stem cells and mesenchymal stem cells in bone marrow decrease with aging (Geiger H et al., Nat Immunol., 3:329-333, 2002), besides the problem that bone marrow extraction is distressing to the patient, which limits the actual clinical application. Thus, alternatives have been searched.
Umbilical cord is the line connecting a mother and the fetus through which nutrition is provided and wastes are excreted, and the blood inside thereof is so-called umbilical cord blood. The umbilical cord blood seems to be the most appropriate alternative of bone marrow in extracting the stem cells of hematopoietic system because it contains more primitive stem cells than those of bone marrow. In addition, such cell extraction is much easier.
The transplantation of hematopoietic stem cells extracted from umbilical cord blood has been clinically applied since 1980s, because of their advantages over bone marrow: higher hematopoietic proliferation activity which means more hematopoietic stem cells present per unit volume (Szilvassy S J et al., Blood, 98:2108-2115, 2001); less HLA (human leukocyte antigen) incompatibility which means less graft versus host reactions (Rocha V et al., N Engl J Med., 342:1846-1854, 2000); easier and less invasive extraction (Rubinstein P et al., N Engl J Med., 339:1565-1577, 1998); and remarkably lower risks compared to those which may be caused by autologous bone marrow transplantation in case of various types of cancer or other diseases. In particular, umbilical cord blood bank has recently been in operation to provide services of preservation and amplification of umbilical cord blood, which has triggered various clinical practices for transplantation of hematopoietic stem cells of umbilical cord blood.
The question has not been settled and public attention has been directed as to whether the mesenchymal stem cells, particularly, MAPC-like cells having excellent differentiation potential into various organ cells are present in umbilical cord blood. This is because it would be a break-through discovery in cell therapy, and cell and tissue regenerative medicine, if mass-production of such mesenchymal stem cells or MAPC-like cells from umbilical cord blood can be achieved. It has been predicted based on the primitiveness of stem cells of umbilical cord blood that MAPC-like cells exist more in umbilical cord blood than in the bone marrow. Recently, mesenchymal stem cells were found present in the umbilical cord blood (Erices A et al., Br J Haematol., 109:235-242, 2000) and it has been proven that the cells have MAPC cell-level multipotency enabling them to differentiate into osteoblasts, adipocytes and neuron-like cells ex vivo (Lee O K et al., Blood., 103:1669-1675, 2004). Further, it was a common belief that the number of mesenchymal cells taken from umbilical cord blood at first was very small and the proliferation thereof was very difficult. But, according to recent reports, it has been proven that ex vivo amplification of the umbilical cord blood-derived mesenchymal stem cells is possible to obtain a large number of mesenchymal stem cell (Yang S E et al, Cytotherapy, 6:476-486, 2004; and Kern S H et al., Stem Cells, 24:1294-1301, 2006).
It has been reported that these cells still possess multipotency even after amplification, and can be differentiated into osteoblasts, chondroblasts, adipocytes and neuron-like cells ex vivo, while differentiating in vivo into nerve cells with the migrating ability, cartilage and bone cells, cells of hematopoietic system and liver cells (Kogler G et al., J Exp Med., 200:123-135, 2004).
Methodologically, the umbilical cord blood extracted from the real placental tissue is an ideal source for autologous and allogeneic stem cells, and such stem cells obtained thereby can be used directly or after amplifying stage whenever and as many as required.
However, there has been no attempt to apply the umbilical cord blood-derived stem cell transplantation to the developmental and/or chronic lung diseases. There are a few experimental reports that the adult bone marrow stem cells transplanted into a mouse with pneumonia induced by irradiation were differentiated into bronchial cells and type II cells of lung parenchyma (Theise N D et al. Exp Hematol., 30:1333-1338, 2002), and reduced the bleomycin-induced pulmonary fibrosis in adult animal models (Ortiz L et al. Proc Natl Acad Sci USA, 100:8407-8411, 2003; and Rojas M et al., Am J Respir Cell Mol Biol, 33:145-152, 2005).
There are some patents aimed for treatment of diseases using the umbilical cord blood-derived cells. For example, Korean Patent Publication No. 2003-0015160 describes a composition for treating articular cartilage damage comprising cell components separated, proliferated or differentiated from the umbilical cord blood and a medium containing thereof, and Korean Patent Publication No. 2005-0105467 describes a method for treating myelodysplastic syndrome and myelosclerosis by administering a high dose of umbilical cord blood-derived stem cells. However, there have been no descriptions on the therapeutic effect of the transplantation of umbilical cord blood-derived stem cells in treating developmental and/or chronic lung diseases.
Thus, the present inventors established a bronchopulmonary dysplasia model by administering highly concentrated oxygen continuously, and then administered umbilical cord blood-derived mesenchymal stem cells to the bronchopulmonary dysplasia model. As a result, pulmonary alveoli were increased in their numbers and developed normally, and the administered cells were differentiated into lung parenchymal cells. Thus, the present inventors have completed this invention by confirming that the umbilical cord blood-derived mesenchymal stem cells of the present invention can be effectively used for the treatment of lung diseases.